(L22) Infection and innate immunity

All living things (expect perhaps viruses) have some ability to discriminate between ___________. CRISP/Cas9 gene editing technology comes from a ____________ to __________

self and non-self, bacteria immune response, bacteriophage infection

Innate immunity provides our ______ or _______ response to pathogen invasion. Very ______ response but unlike adaptive immunity, it does not _____ and has no ________.

first-line, immediate, fast, adapt, memory

3 innate processes that provide immediate immune defence

1. Complement

2. Myeloid cells and phagocytosis (neutrophils and macrophages)

3. Pattern Recognition Receptors (PRR)

Viruses

• Intracellular pathogens

• Defence relies on antibodies and cellular immunity - need to be able to distinguish infected from normal cells from normal cells

Examples of viruses

• Influenza

• Polio

• Smallpox

• Varicella

• HIV

Bacteria

• Extracellular pathogens

• Defence is primarily mediated by innate mechanisms and phagocytosis

Bacteria examples

• Staph aureus

• Mycobacterium (tuberculosis intracellular)

• Strep progenies

• Yersinia pestis

• Vibrio cholarae

Protozoa and parasites

Complex multicellular organisms are too large to be engulfed by phagocytes. Requires direct killing by soluble chemical released by specialist myeloid cells. These mechanisms are fundamentally linked to allergy and inflammation

Granules filled with cytotoxic chemicals such as histamine. Degranulation releases these toxic inflammatory chemicals

Parasite example

Filarial worm

Two types of bacteria distinguished by the Gram stain

• Gram positive

• Gram negative

Gram positive bacteria

Has a thick peptidoglycan cell wall as a defence. Requires phagocytosis and are not killed directly by MAC complement e.g S. aureus, S. progenies

Gram negative bacteria

Has a thin peptidoglycan layer surrounded by a tough outer membrane e.g. E. coli, H. influenza

β-lactam antibiotics such as _________ inhibit the synthesis of peptidoglycan

Penicillin

Neutrophil extravasation - 5 steps

1. Activation

2. Tethering

3. Adhesion

4. Diapadesis

5. Chemotaxis

Activation

Chemokines from opsonization, tissue injury or inflammation activate the local adjacent capillary endothelial cells

Tethering

Neutrophil tethers to the inside capillary wall. Mediated by selectins upregulated on endothelial cells and sialyl Lewis X (sLe^x) a carbohydrate antigen on the surface of neutrophil

Adhesion

Strong binding between neutrophil intentions and ICAM-1 on the endothelium. Neutrophil immobilises and flattens.

Diapadesis

Neutrophil squeezes between endothelial cells into the interstitial space

Chemotaxis

Neutrophil migrates along a chemokine gradient to the site of infection

Neutrophil extravasation takes only _____ form the first point of tissue injury

minutes

Complement initiates…

phagocytosis - opsonization

Anaphylotoxins

potently attract and activate phagocytes

Complement receptors

CR1, CR2, CR3, CR4

Myeloid cell surface receptors bind…

activated complement components that permanently coat the bacteria (opsonised)

Main receptor

CR1 (or C3b) receptor

Cross-linking of the surface CRs on neutrophil initiates…

phagocytosis

C5a receptor is also important that detects C5a and activates the neutrophil

Fc Receptor (antibody) mediated phagocytosis

1. Neutrophils and other phagocytise cells have another important set of receptors called Fc receptors (FcR) that bind bound antibodies

2. Antibody (IgM and IgG) bind to bacterial surface antigenic epitope

3. Exposes the antibody Fc region

4. Neutrophil Fc Receptors binds multivalent Fc

5. Activates phagocytosis

6. Membrane invaginates forming phagosome

7. Fuses with lysosome to form phagolysosome

8. Phagolysosome acidifies and superoxides kill the bacteria

Phagocytosis steps

1. Capture

2. Invagination

3. Phagosome/lysosome fusion

4. Phagolysosome killing

5. Exocytosis

Pathogen Associated Molecular Patterns (PAMPs)

• Molecules that are unique to microbes are recognised by a class of cell surface and intracellular receptors called pattern recognition receptors (PRR)

• Are structurally very complex molecule e.g. lipopolysaccharides

• Are evolutionary stable and essential to the microbe - they don’t change too much (can be easily recognised)

PRRs bridge the innate and adaptive systems providing the ‘_________’ switch for the ________ response - telling the immune system that this really is a pathogen and often what type of pathogen it is and how best to respond

alarm and power, adaptive

• Can tell what type of pathogen for what type of pathway

Pattern recognition receptors

• Best known are the Toll-Like Receptors (TLR) but there are many others

• They bind many different complex PAMPs and often work together

• Activation through TLR stimulates a strong innate response through an important signalling pathway involving a nuclear factor called NFKB (inflammatory)

• TLRs are rich in leucine repeats and look like a coiled spring

Gram-negative has LPS on its outer membrane which recognises

TLR4

• LPS is a membrane component of all _________

• Tiny amounts in your blood stream induce a powerful _______ response

• LPS is a “pyrogen”. It causes a rapid rise in _________ (fever) when tiny amounts are injected in the bloodstream

• LPS is important in the _________ industry. As a common ____________ it must be removed from anything that gets injected into humans

• Release of LPS by Gram negative bacterial infections leads to life treating _________, asteroid outcome of gram negative _________

• gram-negative bacteria

• innate

• temperature

• contaminant, pharmaceutical

• septic shock, sepsis